Nasopharyngeal Cancer 

Updated: Nov 17, 2016
Author: Arnold C Paulino, MD; Chief Editor: Cameron K Tebbi, MD 

Overview

Background

Nasopharyngeal carcinoma is a rare tumor arising from the epithelium of the nasopharynx. It accounts for approximately 1% of all childhood malignancies. Whereas almost all adult nasopharyngeal cancers are carcinomas, only 35-50% of nasopharyngeal malignancies are carcinomas in children. In the pediatric population, additional nasopharyngeal malignancies include rhabdomyosarcomas or lymphomas.

Pathophysiology

The detection of the Epstein-Barr virus (EBV) nuclear antigen and viral DNA in nasopharyngeal carcinoma has revealed that EBV can infect epithelial cells and is associated with their malignant transformation.[1] Copies of the EBV genome have been found in cells of preinvasive lesions, suggesting that it is directly related to the process of transformation.

Epidemiology

Frequency

United States

Although the incidence varies according to geographic location, approximately 1 in every 100,000 children are diagnosed annually in North America.

International

The disease is far more common in children of Southeast Asian and Northern African descent, with an incidence of 8-25 in every 100,000 children annually.

Mortality/Morbidity

When radiotherapy is used alone, survival rates range from 40-50%. Use of combination radiation therapy and chemotherapy allows long-term survival rates of 55-80%.

Race

In the United States, the incidence of nasopharyngeal carcinoma is increased among black teenagers.[2] Children of Asian, Middle Eastern, and Northern African descent are also more commonly affected.

Sex

A male preponderance is observed. The male-to-female ratio is approximately 2:1.

Age

Nasopharyngeal carcinoma has a bimodal age distribution. A small peak is observed in late childhood, and a second peak occurs in people aged 50-60 years. Childhood nasopharyngeal carcinoma is usually a disease of adolescence.[3]

 

Presentation

History

Nasopharyngeal carcinoma rarely comes to medical attention before it has spread to regional lymph nodes. Enlargement and extension of the tumor in the nasopharynx may result in symptoms of nasal obstruction (eg, congestion, nasal discharge, bleeding), changes in hearing (usually associated with blockage of the eustachian tube, but direct extension into the ear is possible), and cranial nerve palsies (usually associated with extension of the tumor into the base of the skull).

One study indicated the following symptoms[4] :

  • Nasal symptoms: including bleeding, obstruction, and discharge (78%)

  • Ear symptoms: including infection, deafness, and tinnitus (73%)

  • Headaches (61%)

  • Neck swelling (63%)

Physical

See the list below:

  • The most common physical finding is a neck mass consisting of painless firm lymph node enlargement (80%).

  • Neck involvement is often bilateral; the most common nodes involved are the jugulodigastric, and upper and middle jugular nodes in the anterior cervical chain.

  • Cranial nerve palsy at initial presentation is observed in 25% of patients.

  • On nasopharyngoscopy, a mass arising in the nasopharynx is often visible. The most frequent site is the fossa of Rosenmüller.

  • A paraneoplastic osteoarthropathy has been described in patients with widespread metastatic or recurrent disease.

Causes

Viral DNA in nasopharyngeal carcinoma has revealed that Epstein-Barr virus (EBV) can infect epithelial cells and is associated with their transformation to cancer.[1] Genetic and environmental factors have been implicated in the development of this disease. A genetic etiology has been considered due to the higher rates of disease within specific ethnic groups, patients with first-degree relatives with the disease, patients with A2 HLA haplotypes, and cytogenetic abnormalities identified within tumor samples.[5, 6] Environmental causes must be considered due to the geographical distribution of the disease, bimodal age distribution, and association seen in patients who consume a large amount of preserved foods and/or salted fish.[7]

 

DDx

 

Workup

Laboratory Studies

See the list below:

  • Perform routine blood work, including a complete blood count and chemistry profile. Liver function test results may be abnormal in those rare cases with hepatic metastases. Uric acid levels may be elevated in patients with rapidly growing tumors.

  • Epstein-Barr virus (EBV) titers, including immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies to the viral capsid antigen, early antigen, and nuclear antigen should be performed. These titers may correlate with tumor burden and decrease with treatment.[8, 9] New data has emerged that plasma EBV-DNA levels may be a helpful marker for pretreatment risk categorization, initial treatment response, and at the time of relapse.[10]

Imaging Studies

See the list below:

  • CT scanning

    • CT scanning of the head and neck is used to determine tumor extent, base of skull erosion, and cervical lymphadenopathy.

    • CT scanning of the chest is used to search for distant metastases.

  • When intracranial extension is suspected, MRI of the head and skull base may better reveal the extent of the tumor.

    MRI of the head and neck in a patient with nasopha MRI of the head and neck in a patient with nasopharyngeal carcinoma showing the primary tumor and cervical lymph node metastases
  • Bone scans are used to search for distant bony metastatic disease.

  • Positron emission tomography (PET) imaging has been used to assess questionable neck nodes and evaluate for other sites of distant disease.

    Intensity modulated radiotherapy images for a pati Intensity modulated radiotherapy images for a patient with nasopharyngeal carcinoma

Other Tests

See the list below:

  • A baseline audiogram is helpful prior to platinum-based chemotherapy and radiotherapy.

  • Creatinine clearance rates (24-hour collection or nuclear GFR testing) should be obtained at baseline and during treatment for those patients being treated with platinum-based chemotherapy because decreases in renal function, requiring dose modifications, have been reported.

Procedures

See the list below:

  • A biopsy of the primary lesion or neck node is obtained for diagnosis.

  • Central line placement is recommended for those children receiving chemotherapy.

  • Because of severe oropharyngeal mucositis that can be seen with radiation therapy, strong consideration of gastrostomy tube placement should happen at diagnosis and/or prior to initiation of radiation therapy in order to sustain proper hydration and nutrition.

Histologic Findings

See the list below:

  • The World Health Organization (WHO) has classified nasopharyngeal carcinoma into 3 categories.

    • WHO-1 is defined as well–to–moderately differentiated squamous or transitional cell carcinoma with keratin production.

    • WHO-2 is nonkeratinizing carcinoma.

    • WHO-3 is undifferentiated carcinoma, including lymphoepithelioma. This entity consists of malignant epithelial cells with lymphocytic infiltration.

  • The vast majority of children are found to have WHO-3 disease.[11, 12]

Staging

Various staging schema have been proposed for nasopharyngeal carcinoma in children.[13] No single system has proven satisfactory in correlating disease extent to prognosis.

Currently, the Seventh Edition of the American Joint Committee on Cancer (AJCC) Staging is used to stage patients with nasopharyngeal cancer. The staging system takes into account the tumor (T), nodal (N) and metastatic (M) extent of the nasopharyngeal cancer.[14]

Table 1. AJCC Staging for Nasopharyngeal Cancer (Open Table in a new window)

Stage

T

N

M

0

Tis

No

M0

I

T1

N0

M0

II

T1

N1

M0

T2

N0

M0

T2

N1

M0

III

T1

N2

M0

T2

N2

M0

T3

N0

M0

T3

N1

M0

T3

N2

M0

IVA

T4

N0

M0

T4

N1

M0

T4

N2

M0

IVB

Any T

N3

M0

IVC

Any T

Any N

MI

 

Table 2. Tumor (T) Staging (Open Table in a new window)

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor confined to the nasopharynx or extends to oropharynx and/or nasal cavity without parapharyngeal extension

T2

Tumor with parapharyngeal extension

T3

Tumor involves bony structures of skull base and/or paranasal sinuses

T4

Tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit, or with extension to the infratemporal fossa/masticator space

 

Table 3. Nodal (N) Staging (Open Table in a new window)

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Unilateral metastasis in cervical lymph node(s), less than or equal to 6 cm in greatest dimension, above the supraclavicular fossa, and/or unilateral or bilateral retropharyngeal lymph nodes, less than or equal to 6 cm in greatest dimension

N2

Bilateral metastasis in a cervical lymph node (s), less than or equal to 6 cm in greatest dimension, above the supraclavicular fossa

N3

Metastasis in a lymph node(s) greater than 6 cm and/or to supraclavicular fossa

N3a

Greater than 6 cm in dimension

N3b

Extension to supraclavicular fossa

Table 4. Metastasis (M) Staging (Open Table in a new window)

M0

No distant metastasis

M1

Distant metastasis

 

 

Treatment

Medical Care

Radiation therapy is the mainstay of treatment, with chemotherapy used in advanced cases. Concurrent cisplatin, 5-fluorouracil, and radiotherapy have been shown to improve survival.[15, 16, 17] Sequential chemoradiotherapy with gemcitabine and cisplatin has been shown to improve survival in locoregionally advanced nasopharyngeal carcinoma.[18] Many pediatric studies have used neoadjuvant chemotherapy followed by radiation therapy with improvement in local control or progression-free survival rates over radiotherapy alone.[19, 20, 21]

In November 2016, nivolumab (Opdivo) was approved by the FDA for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy. Nivolumab is a monoclonal antibody that inhibits PD-1 and blocks interaction between PD-1 and its ligands, PD-L1 and PD-L2. It’s approval was based on the phase 3 CheckMate-141 trial. Results from the trial showed nivolumab significantly improved overall survival when compared with the comparator (investigator's choice of methotrexate, docetaxel, or cetuximab). The median overall survival was 7.5 months for nivolumab compared with 5.1 months for investigator's choice (hazard ratio, 0.70; P = .0101) , and the estimates for the 1-year survival rate were 36% with nivolumab vs 16.6% with investigator's choice. The trial was stopped early after this benefit was shown in a preplanned analysis.[22]

Radiotherapy is administered to the gross tumor volume (GTV) or disease in the primary site and neck adenopathy. The initial clinical target volume (CTV) includes the GTV and all sites of potential subclinical disease to a dose of 45-50.4 Gy at 1.8-2 Gy/fraction. It is anticipated that in most patients, levels I to V neck nodes are included in the initial CTV. For the boost CTV, the GTV with a margin is treated to a dose of 15-25 Gy. The total dose to the GTV usually ranges from 65-70 Gy. A planning target volume (PTV) takes into account the CTV and daily set-up variation; in most cases with an immobilization mask for the head and neck, a 0.5-cm margin is added to the CTV to create the PTV. The PTV receives the same prescription dose as the CTV.

In the past, the initial radiotherapy fields were treated with 2 parallel opposed lateral fields that encompassed the nasopharynx and upper cervical nodes. The lower cervical nodes were treated with an anterior field, which abuts the upper lateral fields superiorly. These patients are now commonly treated with intensity-modulated radiation therapy (IMRT). IMRT may be used to spare neighboring critical structures next to the nasopharynx, such as the brain, pituitary gland, optic chiasm, optic nerve, and spinal cord.

A randomized controlled trial compared the clinical outcomes of upper versus whole-neck prophylactic irradiation in the treatment of patients with node-negative nasopharyngeal carcinoma (NPC). The study concluded that prophylactic upper neck irradiation is sufficient for patients with node-negative NPC. Larger studies are needed to confirm the study’s findings.[23]

A multi-institutional study showed that doses of at least 66 Gy to gross disease are needed for optimal local control.[24] Others have used a radiotherapy dose adaptation strategy with which children responding well to chemotherapy receive less radiotherapy dose. In the Italian Rare Tumors in Pediatric age (TREP) Project, 3 courses of cisplatin and 5-fluorouracil followed by radiotherapy, with doses ranging from 60-65 Gy to gross disease, resulted in a 5-year progression-free survival rate of 79.3%.[25] In another study, cervical nodal irradiation was reduced to less than 50 Gy, with good response to chemotherapy (>90% shrinkage of original tumor) with a 5-year, event-free survival rate of 75%.[26]

Data using IMRT reveal equivalent or better locoregional control compared with conventional radiotherapy and sparing of the parotid glands from high doses of radiation therapy.[27, 28]

During the course of radiotherapy, several immediate effects may occur, usually after the first 2 weeks of treatment. Confluent mucositis usually occurs, especially in children receiving both radiotherapy and cisplatin. Dry mouth and thick saliva are also likely secondary to irradiation of the salivary glands. Because of this oropharyngeal mucositis, consideration of placement of a gastrostomy tube prior to initiation of radiotherapy. If a gastrostomy tube is not placed, poor nutrition and dehydration are quite common, and intravenous fluids may need to be administered. Redness, itching, and peeling of the treated skin can occur towards the end of radiotherapy and may need to be treated with topical antibiotics and Silvadene. A study of children treated with IMRT showed less acute toxicity (skin, mucous membrane, pharynx) compared with conventional radiotherapy.[29]

Some centers use amifostine, a radioprotective agent, to help reduce radiation-related xerostomia. Possible adverse effects of amifostine such as flulike symptoms, nausea, low calcium levels, and hypotension have limited its widespread use in the oncologic community.

Surgical Care

Surgical therapy for these patients is often limited to a biopsy for tissue diagnosis. Nearly all tumors are unresectable at diagnosis because of their location.

Consultations

Consultation with an otolaryngologist is often required in the initial management to obtain tissue diagnosis and in follow-up endoscopic examinations to rule out recurrence. An otolaryngologist may also be involved if the child develops sensorineural hearing loss from cisplatin and radiotherapy.

Consultation with an endocrinologist may be required in the future if the child shows signs of growth retardation or hypothyroidism secondary to radiotherapy.[27] Occasionally, children develop panhypopituitarism.

Consultation with a dentist familiar with radiation effects should be performed prior to initiation of radiotherapy to minimize risk of osteoradionecrosis. Patients also need to be followed after treatment as xerostomia and change in salivary consistency may predispose the patient to dental caries.

Diet

Many patients experience severe mucositis during radiotherapy. Certain foods may irritate irradiated mucosa, causing pain or difficulty swallowing or chewing. Soft foods such as milkshakes, mashed potatoes, and pureed meats are advisable during the course of radiotherapy. Citrus fruits, spicy foods, salty foods, and coarse foods can make the irritated mucosa worse. Gastrostomy tube placement allows adequate hydration and calorie intake during radiotherapy.

Activity

Activity depends on the child's condition. During periods of chemotherapy-induced thrombocytopenia, some limitation of strenuous activity and avoidance of contact sports is necessary. Infectious contacts should be avoided where possible, especially during periods of neutropenia.

 

Medication

Medication Summary

Medical therapy consists of radiation therapy and chemotherapy. Concurrent treatment with cisplatin, 5-fluorouracil, and radiotherapy has been shown to improve survival rates. Other studies have used neoadjuvant chemotherapy followed by radiation therapy with improvement in local control or progression-free survival rates.

In November 2016, nivolumab was approved for SCCHN that has advanced on or after platinum-based therapy. Nivolumab significantly improved overall survival when compared with the comparator (investigator's choice of methotrexate, docetaxel, or cetuximab) in the phase 3 CheckMate-141 trial.[22]

Anesthetic lozenges and sprays may be helpful during the course of radiotherapy to minimize oral or throat pain, and pilocarpine with or without artificial salivary products (ie, oral sprays, gels, gums) may improve radiation-associated xerostomia.

Antineoplastic agents

Class Summary

Chemotherapy is used to decrease the bulk of disease and to limit the risk of recurrence. Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2); then, finally a mitotic cell division (ie, phase M) occurs.

Cell division rate varies for different tumors. Most common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly than malignant ones from chemotherapy and is the rationale behind current cyclic dosage schedules. Dosage cycles are determined by cancer stage and tolerance of adverse effects.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Cisplatin (Platinol)

Inhibits DNA synthesis and, thus, cell proliferation by causing DNA crosslinks and denaturation of double helix.

5-Fluorouracil (5-FU, Adrucil)

Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase and also interferes with RNA synthesis and function. Has some effect on DNA. Useful in symptom palliation for patients with progressive disease.

PD-1/PD-L1 Inhibitors

Class Summary

PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells.

Nivolumab (Opdivo)

Nivolumab is a monoclonal antibody to programmed cell death-1 protein (PD-1); blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is indicated for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy.

Antiemetic agents

Class Summary

Prevention and treatment of chemotherapy-induced nausea and vomiting. Prevention is essential for highly emetogenic drugs (eg, cisplatin-based chemotherapy).

Antineoplastic-induced vomiting is stimulated through the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center (VC) in the brain. Increased activity of central neurotransmitters, dopamine in CTZ, or acetylcholine in VC appears to be a major mediator for inducing vomiting. Following administration of antineoplastic agents, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With serotonin release and subsequent binding to 5-HT3-receptors, vagal neurons are stimulated and transmit signals to the VC, resulting in nausea and vomiting.

Antineoplastic agents may cause nausea and vomiting so intolerable that patients may refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents prior to and following cancer treatment is often essential to ensure administration of the entire chemotherapy regimen.

Ondansetron (Zofran)

Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and complete body radiotherapy.

Colony-stimulating factors

Class Summary

These agents act as a hematopoietic growth factor that stimulates the development of granulocytes. They are used to treat or prevent neutropenia in patients receiving myelosuppressive cancer chemotherapy and to reduce the period of neutropenia associated with bone marrow transplantation. They are also used to mobilize autologous peripheral blood progenitor cells for bone marrow transplantation and in the management of chronic neutropenia.

Filgrastim (G-CSF, Neupogen)

Granulocyte colony-stimulating factor that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils. Is most often administered to prevent neutropenia, starting 1 d after completion of highly myelosuppressive chemotherapy. Can also be used to treat neutropenia in the setting of significant infection.

 

Follow-up

Further Outpatient Care

Radiation therapy is often administered on an outpatient basis. Follow-up is necessary after all radiation and chemotherapy has been administered.

Patients are evaluated every 3 months during the first year and every 6 months during the second and third years after treatment. Thereafter, follow-up is necessary every year.

Physical examination and a detailed history should be performed with each visit.

Imaging of the head and neck (CT or MRI), CT of the chest, and bone scan/positron emission tomography (PET) (if positive at distant metastatic sites at diagnosis) are usually performed every 3 months for the first year and then every 6 months for the next 2 years after therapy is completed to assess response.

A dental examination prior to radiotherapy and on a routine basis after therapy is recommended because of the possibility of caries and poor dental hygiene. Osteonecrosis of the mandible is a rare complication of radiotherapy and is often avoided with proper dental care.

As many children develop endocrine abnormalities after treatment, screening testing for hypothyroidism, growth hormone deficiency, and adrenal axis disorders should occur on a frequent basis after the completion of therapy.

Further Inpatient Care

See the list below:

  • Certain types of chemotherapy will need to be administered on an inpatient basis.

  • Patients who develop febrile neutropenia need to be admitted for intravenous antibiotics. The antibiotic regimen usually consists of an antipseudomonal cephalosporin, with or without an aminoglycoside (especially in the context of renal dysfunction seen in patients receiving platinum-based chemotherapy) and/or an antistaphylococcal coverage.

  • Severe cases of malnutrition and dehydration may require inpatient management with support from a pediatric nutritionist.

Inpatient & Outpatient Medications

Routine medications are not often administered and depend on treatment-related symptomatology.

Pneumocystis jiroveci pneumonia (also known as PCP) prophylaxis is recommended once chemotherapy starts and until 3 months after therapy is completed.

Annual influenza vaccination (inactivated or killed vaccine, also know as the "flu shot") is recommended for every pediatric patient.

Amifostine (Ethyol) may be used in the management of patients with nasopharyngeal cancer. This drug has been found to reduce xerostomia resulting from radiotherapy and nephrotoxicity resulting from cisplatin chemotherapy.

Pentoxifylline has been used for treatment of radiation-induced fibrosis.[30]

Complications

See the list below:

  • Late toxicity of radiotherapy may include xerostomia, hypothyroidism, fibrosis of the neck with complete loss of range of motion, trismus, dental abnormalities, and hypoplasia of irradiated muscular and bony structures. Because of the high doses of radiotherapy used in this disease, these late toxicities can be significant, especially in younger children.

  • Endocrinopathies and growth retardation can occur secondary to radiotherapy to the pituitary gland. Panhypopituitarism can occur in some instances.

  • Sensorineural hearing loss may occur with the use of cisplatin and radiotherapy.[31]

  • Renal toxicity can occur in patients receiving cisplatin.

  • Caries and poor dental hygiene are associated complications. Osteonecrosis of the mandible is a rare complication of radiotherapy and is often avoided with proper dental care.

  • Second malignancy may occur in a child who has received previous radiotherapy. This risk is small but continues throughout life.

  • With proper radiotherapy techniques, the chance for development of radiation myelitis should be less than 1%.

Prognosis

See the list below:

  • The results of clinical trials that include both radiation therapy and chemotherapy generally report long-term survival rates of 50-80% overall.[15, 32, 33]

  • In a study by Serin et al, the 5-year overall survival rate was 42% with radiotherapy alone and 58% with chemoradiation.[34]

  • Rodriguez-Galindo et al reported a 4-year event-free and overall survival rate of 77% and 75%, respectively, in a Phase II Pediatric Oncology Group clinical trial using radiation alone for patients with T1-T2N0M0 disease and radiation with neoadjuvant chemotherapy for all others.[20] Most were treated with 4 cycles of chemotherapy consisting of methotrexate, cisplatin, 5-fluorouracil, and leucovorin prior to radiotherapy.

Patient Education

See the list below:

  • Patients and parents should be educated regarding the importance of follow-up after completion of all therapy. A detailed discussion of the risks of chemotherapy, especially the risk of febrile neutropenia, is necessary. Families should also be well informed of the issues of late effects.

  • For excellent patient education resources, visit eMedicineHealth's Cancer Center. Also, see eMedicineHealth's patient education article Cancer of the Mouth and Throat.